Compounds and methods for the treatment of alzheimer&#39;s disease and/or cerebral amyloid angiopathy

ABSTRACT

Described herein are novel compounds and methods for the treatment and/or prevention of cerebral amyloidoses such as Alzheimer&#39;s disease (AD) and/or cerebral amyloid angiopathy (CAA).

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. § 119(e) to U.S.Provisional Application No. 62/266,760, filed Dec. 14, 2015, the entirecontents of which are incorporated herein by reference in theirentirety.

TECHNICAL FIELD

The present invention generally pertains to the treatment of humancerebral amyloidoses such as Alzheimer's disease and/or cerebral amyloidangiopathy.

BACKGROUND

Alzheimer's disease is one of the largest socioeconomic healthcareburdens. Alzheimer's disease is characterized by progressive dementiaand histopathologically by the presence of neurofibrillary tangles(NFTs) and neuritic (senile) plaques. Plaques consist of a proteincalled amyloid-beta (Aβ) and tangles are made up of a protein calledtau.

Amyloid plaques and NFTs are both hallmarks of Alzheimer's disease (AD).Mutations in amyloid precursor protein (APP) and presenilin lead toearly onset forms of Alzheimer's disease, supporting the hypothesis thatthe processing of APP may also play an important role in thepathogenesis of sporadic AD. Furthermore, the “amyloid hypothesis”predicts that the accumulation of Aβ in some toxic form is harmful tothe brain. APP can be processed by α- and β-secretase pathways. To date,most research efforts to develop AD therapies that retard theprogression of the disease are focused on inhibition of γ-secretase andβ-secretase and the metabolism of APP to form Aβ peptide or activationof α-secretase processing to increase production of the neuroprotectivesAPPα peptide while reducing Aβ production. Developing specificβ-secretase inhibitors has been difficult, in part because there appearsto be a nonlinear relationship between decrease of β-secretase activityin vivo, and a reduction of Aβ peptides in the brain. A furtherdifficulty is the low brain penetration of most inhibitors, γ-secretaseinhibitors have been further plagued with severe GI side effectsassociated with notch inhibition since γ-secretase processes numerousother substrates in addition to APP, including the notch receptor.Additionally, a deficiency of γ-secretase activity has been shown tocause neurodegeneration and may be associated with autosomal-dominantearly-onset Alzheimer's disease caused by mutations in presenilin 1 (acomponent of the γ-secretase complex that contains the active site ofthe γ-secretase complex).

The majority of efforts aimed at treating Alzheimer's disease havefocused on reducing the symptoms of AD. In particular, identification ofa lower concentration of choline acetyltransferase in affected neuronsof the forebrains of AD patients has led to treatments aimed atinhibiting the hydrolysis of acetylcholine in the synaptic cleft andprolonging the level of acetylcholine at the synapse. Although thisstrategy has resulted in at least a partial correction ofneurotransmitter levels, the therapeutic benefits have been small.

Further, AD is categorized as a tauopathy. Tauopathies are caused byabnormal hyperphosphorylation of tau promoting its aggregation andformation of NFTs. Since mutations in tau and APP both cause dementia,one or both may contribute to the disease progression of AD. It is wellunderstood that mutations leading to altered processing of APP cause AD.Currently, there are no approved therapies for slowing the progressionof Alzheimer's disease. Thus, there remains a need for more beneficialAD treatments. While most therapies in development are focused onaltering APP metabolism (e.g. β-secretase and γ-secretase inhibition) orblocking tau aggregation, the present invention provides a treatmentusing pharmacological chaperones which bind to one or moregangliosidases and/or sialidases and thereby increase the production ofsAPPα and reduce the production of Aβ and hyperphosphorylated tau.

Similarly, cerebral amyloid angiopathy (CAA) is a disorder characterizedby amyloid deposition in the walls of blood vessels of the centralnervous system, particularly in the leptomeningeal and corticalarteries. CAA occurs mostly as a sporadic condition in the elderly, andits incidence is associated with advancing age. These sporadic CAA casesare due to deposition of AP, originating from proteolytic cleavage ofAPP. Hereditary forms of CAA are generally familial, more severe andearlier in onset than sporadic CAA. CAA has also recently beenrecognized as a potential contributor to the development of AD.

SUMMARY

It has been found that pharmacological chaperones that targetβ-hexosaminidase (β-hex) can have many benefits, including use in thetreatment and/or prevention of cerebral amyloidoses such as Alzheimer'sdisease (AD) and/or cerebral amyloid angiopathy (CAA). There is a needfor novel compounds that are pharmacological chaperones for β-hex and/ormay be used in the synthesis of compounds that are chaperones for β-hex.

Accordingly, one aspect of the present invention pertains to a compoundhaving a structure represented by formula I or IA:

-   -   wherein: R¹, R², R⁴ are independently chosen from H, C₁-C₈        alkyl, aryl, (CH₂)_(n) aryl, (CH₂)_(n) heteroaryl;        -   n=0-8;        -   X¹, X² are independently chosen from CO, SO, SO₂, —CONH—,            SO₂NH—, SONH—; and        -   A¹, A², B¹, B², C¹, C² are independently chosen from H, OR⁴,            F,    -   with the proviso that the compound is not        2-acetamido-1,2-dideoxynojirimycin or        2-acetamido-1,2-dideoxygalactonojirimycin,        or a pharmaceutically acceptable salt, solvate, or prodrug        thereof.

In some embodiments, R⁴ is H or benzyl. In particular embodiments, thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Another aspect of the present invention pertains to a compound having astructure represented by formula II or IIA:

-   -   wherein: R¹, R³, R⁴ are independently chosen from H, C₁-C₈        alkyl, aryl, (CH₂)_(n) aryl, (CH₂)_(n) heteroaryl;        -   n=0-8;        -   X═CO, SO, SO₂, —CONH—, SO₂NH—, SONH—;        -   Y═O, S, NH; and        -   A¹, A², B¹, B², C¹, C² are independently chosen from H, OR⁴,            F,            or a pharmaceutically acceptable salt, solvate, or prodrug            thereof.

In some embodiments, R⁴ is H or benzyl. In particular embodiments, thecompound has the following structure:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Another aspect of the present invention pertains to a compound having astructure represented by formula III:

-   -   wherein: R³, R⁴ are independently chosen from H, C₁-C₈ alkyl,        aryl, (CH₂)_(n) aryl, (CH₂)_(n) heteroaryl;        -   n=0-8;        -   Y═O, S, NH; and        -   A¹, A², B¹, B², C¹, C² are independently chosen from H, OR⁴,            F, with the proviso that the compound is not            N-acetyl-glucosaminethiazoline,            or a pharmaceutically acceptable salt, solvate, or prodrug            thereof.

In some embodiments, R⁴ is H or benzyl. In particular embodiments, thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Another aspect of the present invention pertains to a pharmaceuticalcomposition comprising a compound according to any of the abovecompounds; and at least one pharmaceutically acceptable carrier. In yetanother aspect, the invention relates to a method of making thepharmaceutical composition. In one or more embodiments, the methodcomprises adding to at least one pharmaceutically acceptable carrier acompound having a structure represented by any of formulae I-III.

Yet another aspect of the present invention pertains to a method ofpreventing and/or treating cerebral amyloidoses such as Alzheimer'sdisease (AD) and/or cerebral amyloid angiopathy (CAA). In one or moreembodiments, the method comprises administering to a patient in needthereof a therapeutically effective amount of a compound having astructure represented by any of formulae I-III. In some embodiments, theadministration of an effective amount of the compound increasesprocessing of one or more gangliosides selected from GM2 and GA2.

Another aspect of the present invention pertains to a method forenhancing the activity of β-hexosaminidase, the method comprisingadministering an effective amount of a compound having a structurerepresented by any of formulae I-III.

Yet another aspect of the present invention pertains to a kit comprisinga compound having a structure represented by any of formulae I-III, andinstructions for using the compound to treat and/or prevent Alzheimer'sdisease and/or cerebral amyloid angiopathy.

DETAILED DESCRIPTION Definitions

The terms used in this specification generally have their ordinarymeanings in the art, within the context of this invention and in thespecific context where each term is used. Certain terms are discussedbelow, or elsewhere in the specification, to provide additional guidanceto the practitioner in describing the invention and how to make and usethe invention.

As used herein, the term “pharmacological chaperone,” or sometimes“specific pharmacological chaperone” (“SPC”), refers to a molecule thatspecifically binds to a protein, particularly an enzyme, and has one ormore of the following effects: (i) enhancing the formation of a stablemolecular conformation of the protein (both wild-type and mutantproteins); (ii) enhances proper trafficking of the protein from theendoplasmic reticulum (ER) to another cellular location, preferably anative cellular location, i.e., preventing ER-associated degradation ofthe protein; (iii) preventing aggregation of conformationally unstable,i.e., misfolded proteins; (iv) restoring or enhancing at least partialwild-type function, stability, and/or activity of the protein; and/or(v) improving the phenotype or function of the cell harboring a mutantprotein. Thus, a pharmacological chaperone is a molecule thatspecifically binds to a protein, resulting in proper folding,trafficking, non-aggregation, and/or activity of that protein. In thecontext of the present invention, the specific pharmacologicalchaperones are substrates, or substrate analogs or derivatives, of theenzymes.

The wild-type activity/amount can be increased in vivo and/or forco-formulation for ERT. The mutant can be stabilized/enhanced in vivothrough the endoplasmic reticulum, etc. Both mutant and wild typeproteins in the same patient can be stabilized if both are present (suchas the case with X-linked diseases). Thus, one or more embodiments ofthe invention pertain to enhancement of the enzyme (recombinant ornative/mutant) and different types of administration (co-formulationwith recombinant, co-administration with recombinant, monotherapy forthe mutant enzyme that is endogenously produced, and any combination ofthe above.)

As used herein, the term “substrate” refers to a molecule that is actedupon (i.e., modified) by an enzyme. According to the present invention,this term refers to an enzyme's natural or physiological substrate thatis unmodified by human intervention.

The term “β-hexosaminidase” (β-Hex) includes all three isoforms of theenzyme, including β-hexosaminidase A, β-hexosaminidase B andβ-hexosaminidase S. β-hexosaminidase catabolizes GM2 gangliosides andits deficiency causes the autosomal recessive lysosomal storagedisorders Tay-Sachs disease and Sandhoff disease. β-hexosaminidase A iscomposed of an α-subunit and a β-subunit (αβ), β-hexosaminidase B iscomposed of two β-subunits (ββ) and β-hexosaminidase S is composed oftwo α-subunits (αα). The compounds and methods disclosed herein may acton only one isoform of the enzyme, two of the isoforms or all three ofthe isoforms.

The terms “therapeutically effective dose” and “effective amount” referto the amount of the specific pharmacological chaperone that issufficient to result in a therapeutic response. A therapeutic responsemay be any response that a user (e.g., a clinician) will recognize as aneffective response to the therapy, including the foregoing symptoms andsurrogate clinical markers. Thus, a therapeutic response will generallybe an amelioration of one or more symptoms of a disease or disorder,e.g., a lysosomal storage disease, such as those known in the art forthe disease or disorder, e.g., neurological symptoms.

The phrase “pharmaceutically acceptable” refers to molecular entitiesand compositions that are physiologically tolerable and do not typicallyproduce untoward reactions when administered to a human. Preferably, asused herein, the term “pharmaceutically acceptable” means approved by aregulatory agency of the federal or a state government or listed in theU.S. Pharmacopeia or other generally recognized pharmacopeia for use inanimals, and more particularly in humans. The term “carrier” refers to adiluent, adjuvant, excipient, or vehicle with which the compound isadministered. Such pharmaceutical carriers can be sterile liquids, suchas water and oils. Water or aqueous saline solutions and aqueousdextrose and glycerol solutions are preferably employed as carriers,particularly for injectable solutions. Suitable pharmaceutical carriersare described in “Remington's Pharmaceutical Sciences” by E. W. Martin,18th Edition, or other editions.

As used herein, “aryl” refers to aromatic radicals having in the rangeof about 6 to about 14 carbon atoms such as phenyl, naphthyl,tetrahydronapthyl, indanyl, biphenyl. The term “arylalkyl” refers to anaryl group as defined above directly bonded to an alkyl group, e.g.,—CH₂C₆H₅, and —C₂H₄C₆H₅.

Compounds

One aspect of the invention pertains to a compound having a structurerepresented by formula I or IA:

-   -   wherein: R¹, R², R⁴ are independently chosen from H, C₁-C₈        alkyl, aryl, (CH₂)_(n) aryl, (CH₂)_(n) heteroaryl;        -   n=0-8;        -   X¹, X² are independently chosen from CO, SO, SO₂, —CONH—,            SO₂NH—, SONH—; and        -   A¹, A², B¹, B², C¹, C² are independently chosen from H, OR⁴,            F.

In certain embodiments, the compound of formula I or IA is not2-acetamido-1,2-dideoxynojirimycin (AdDNJ) and/or the compound is not2-acetamido-1,2-dideoxygalactonojirimycin (AdDGJ).

Embodiments of the present invention also relate to pharmaceuticallyacceptable salts, solvates, or prodrugs of the compounds of formula I orIA.

In some embodiments, R⁴ is H or benzyl. In particular embodiments, thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Another aspect of the present invention pertains to a compound having astructure represented by formula II or IIA:

-   -   wherein: R¹, R³, R⁴ are independently chosen from H, C₁-C₈        alkyl, aryl, (CH₂)_(n) aryl, (CH₂)_(n) heteroaryl;        -   n=0-8;        -   X═CO, SO, SO₂, —CONH—, SO₂NH—, SONH—;        -   Y═O, S, NH; and        -   A¹, A², B¹, B², C¹, C² are independently chosen from H, OR⁴,            F.

Embodiments of the present invention also relate to pharmaceuticallyacceptable salts, solvates, or prodrugs of the compounds of formula IIor IIA.

In some embodiments, R⁴ is H or benzyl. In particular embodiments, thecompound has the following structure:

or is a pharmaceutically acceptable salt, solvate, or prodrug thereof.

Another aspect of the present invention pertains to a compound having astructure represented by formula III:

-   -   wherein: R³, R⁴ are independently chosen from H, C₁-C₈ alkyl,        aryl, (CH₂)_(n) aryl, (CH₂)_(n) heteroaryl;        -   n=0-8;        -   Y═O, S, NH; and        -   A¹, A², B¹, B², C¹, C² are independently chosen from H, OR⁴,            F.

In certain embodiments, the compound of formula III is notN-acetyl-glucosaminethiazoline.

Embodiments of the present invention also relate to pharmaceuticallyacceptable salts, solvates, or prodrugs of the compounds of formula III.

In some embodiments, R⁴ is H or benzyl. In particular embodiments, thecompound is selected from the group consisting of:

or a pharmaceutically acceptable salt, solvate, or prodrug thereof.Synthesis

Another aspect of the invention pertains to methods of producing theabove compounds. Scheme I below provides prophetic syntheses forexemplary compounds of formulae I and IA:

Based on the above Scheme I, one of ordinary skill in the art canproduce the compounds according to formulae I and IA by selectingdifferent appropriate starting compounds.

Scheme II below provides a prophetic synthesis for exemplary compoundsof formulae II and IIA:

Based on the above Scheme II, one of ordinary skill in the art canproduce the compounds according to formulae II and IIA by selectingdifferent appropriate starting compounds.

Scheme III below provides prophetic syntheses for exemplary compounds offormula III:

Based on the above Scheme III, one of ordinary skill in the art canproduce the compounds according to formula III by selecting differentappropriate starting compounds.

Compositions/Formulations

Other aspects of the invention pertain to compositions/formulationscomprising any of the compounds described herein. Accordingly, one ormore embodiments of the invention pertain to a pharmaceuticalcomposition or formulation comprising: any of the compounds according toany of formulae I-III, or a pharmaceutically acceptable salt, solvate,or prodrug thereof; and at least one pharmaceutically acceptablecarrier. The pharmaceutical composition may be prepared by adding acompound according to any of formulae I-III, or a pharmaceuticallyacceptable salt, solvate, or prodrug thereof to at least onepharmaceutically acceptable carrier.

Compounds of the present invention include pharmaceutically acceptablesalts, solvates and pro-drugs of the compounds disclosed herein.Pharmaceutically acceptable salts include salts derived from inorganicbases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; salts of organic basessuch as N,N′-diacetylethylenediamine, glucamine, triethylamine, choline,hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine,thiamine; chiral bases like alkylphenylamine, glycinol, phenyl glycinol,salts of natural amino acids such as glycine, alanine, valine, leucine,isoleucine, norleucine, tyrosine, cystine, cysteine, methionine,proline, hydroxy proline, histidine, omithine, lysine, arginine, serine;non-natural amino acids such as D-isomers or substituted amino acids;guanidine, substituted guanidine wherein the substituents are selectedfrom nitro, amino, alkyl, alkenyl, alkynyl, ammonium or substitutedammonium salts and aluminum salts. Salts may include acid addition saltswhere appropriate which are, hydrochlorides, sulphates, nitrates,phosphates, perchlorates, borates, hydrohalides, acetates, tartrates,maleates, citrates, succinates, palmoates, methanesulphonates,benzoates, salicylates, benzenesulfonates, ascorbates,glycerophosphates, ketoglutarates. In one embodiment, thepharmaceutically acceptable salt of the compounds disclosed herein isthe hydrochloride salt.

“Solvate” denotes a physical association of a compound with one or moresolvent molecules. This physical association involves varying degrees ofionic and covalent bonding, including hydrogen bonding. In certaininstances the solvate will be capable of isolation, for example when oneor more solvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. “Hydrate” is a solvate wherein the solvent moleculeis H₂O. Other non-limiting examples of suitable solvates includealcohols (e.g., ethanolates, methanolates, and the like).

Prodrugs are compounds which are converted in vivo to active forms (see,e.g., R. B. Silverman, 1992, “The Organic Chemistry of Drug Design andDrug Action”, Academic Press, Chapter 8, incorporated herein byreference). Additionally, a discussion of prodrugs is provided in T.Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Volume 14 ofthe A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencethereto. Prodrugs can be used to alter the biodistribution (e.g., toallow compounds which would not typically enter the reactive site of theprotease) or the pharmacokinetics for a particular compound. Forexample, a carboxylic acid group, can be esterified, e.g., with a methylgroup or an ethyl group to yield an ester. When the ester isadministered to a subject, the ester is cleaved, enzymatically ornon-enzymatically, reductively, oxidatively, or hydrolytically, toreveal the anionic group. An anionic group can be esterified withmoieties (e.g., acyloxymethyl esters) which are cleaved to reveal anintermediate compound which subsequently decomposes to yield the activecompound.

Examples of prodrugs and their uses are well known in the art (See,e.g., Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19). The prodrugs can be prepared in situ during the finalisolation and purification of the compounds, or by separately reactingthe purified compound with a suitable derivatizing agent. For examplehydroxy groups can be converted into esters via treatment with acarboxylic acid in the presence of a catalyst. Examples of cleavablealcohol prodrug moieties include substituted and unsubstituted, branchedor unbranched lower alkyl ester moieties, (e.g., ethyl esters), loweralkenyl esters, di-lower alkyl-amino lower-alkyl esters (e.g.,dimethylaminoethyl ester), acylamino lower alkyl esters, acyloxy loweralkyl esters (e.g., pivaloyloxymethyl ester), aryl esters (phenylester), aryl-lower alkyl esters (e.g., benzyl ester), substituted (e.g.,with methyl, halo, or methoxy substituents) aryl and aryl-lower alkylesters, amides, lower-alkyl amides, di-lower alkyl amides, and hydroxyamides.

The compounds of the present invention can be formulated to be suitablefor any route of administration, including e.g., orally in the form oftablets or capsules or liquid, or in sterile aqueous solution forinjection. When the compound is formulated for oral administration,tablets or capsules can be prepared by conventional means withpharmaceutically acceptable excipients such as binding agents (e.g.,pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose orcalcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talcor silica); disintegrants (e.g., potato starch or sodium starchglycolate); or wetting agents (e.g., sodium lauryl sulphate). Thetablets may be coated by methods well known in the art. Liquidpreparations for oral administration may take the form of, for example,solutions, syrups or suspensions, or they may be presented as a dryproduct for constitution with water or another suitable vehicle beforeuse. Such liquid preparations may be prepared by conventional means withpharmaceutically acceptable additives such as suspending agents (e.g.,sorbitol syrup, cellulose derivatives or hydrogenated edible fats);emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles(e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetableoils); or preservatives (e.g., methyl or propyl-p-hydroxybenzoates orsorbic acid). The liquid preparations may also contain buffer salts,flavoring, coloring or sweetening agents as appropriate. Preparationsfor oral administration may be suitably formulated to give controlled orsustained release of the compound.

In some embodiments, the route of administration is subcutaneous. Otherroutes of administration may be oral or parenteral, includingintravenous, intra-arterial, intraperitoneal, ophthalmic, intramuscular,buccal, rectal, vaginal, intraorbital, intracerebral, intradermal,intracranial, intraspinal, intraventricular, intrathecal,intracisternal, intracapsular, intrapulmonary, intranasal, transmucosal,transdermal, or via inhalation

In one or more embodiments of the present invention, the compound isadministered in a dosage form that permits systemic distribution oruptake, such that the compound may cross the blood-brain barrier so asto exert effects on neuronal cells. Such dosage forms that permitsystemic distribution or uptake may be oral or parenteral. In someembodiments, the compound may be distributed systemically, includingcrossing the blood-brain barrier.

For example, pharmaceutical formulations of the compound suitable forparenteral/injectable use generally include sterile aqueous solutions(where water soluble), or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersion. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (for example, glycerol, propylene glycol,polyethylene glycol, and the like), suitable mixtures thereof, orvegetable oils. The proper fluidity can be maintained, for example, bythe use of a coating such as lecithin, by the maintenance of therequired particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms can be broughtabout by various antibacterial and antifungal agents, for example,parabens, chlorobutanol, phenol, benzyl alcohol, sorbic acid, and thelike. In many cases, it will be reasonable to include isotonic agents,for example, sugars or sodium chloride. Prolonged absorption of theinjectable compositions can be brought about by the use in thecompositions of agents delaying absorption, for example, aluminummonosterate or gelatin.

Sterile injectable solutions are prepared by incorporating the compoundin the required amount in the appropriate solvent with various of theother ingredients enumerated above, as required, followed by filter orterminal sterilization. Generally, dispersions are prepared byincorporating the various sterilized active ingredients into a sterilevehicle which contains the basic dispersion medium and the requiredother ingredients from those enumerated above. In the case of sterilepowders for the preparation of sterile injectable solutions, thepreferred methods of preparation are vacuum drying and the freeze-dryingtechnique which yield a powder of the active ingredient plus anyadditional desired ingredient from previously sterile-filtered solutionthereof.

The formulation can contain an excipient. Pharmaceutically acceptableexcipients which may be included in the formulation are buffers such ascitrate buffer, phosphate buffer, acetate buffer, and bicarbonatebuffer, amino acids, urea, alcohols, ascorbic acid, phospholipids;proteins, such as serum albumin, collagen, and gelatin; salts such asEDTA or EGTA, and sodium chloride; liposomes; polyvinylpyrollidone;sugars, such as dextran, mannitol, sorbitol, and glycerol; propyleneglycol and polyethylene glycol (e.g., PEG-4000, PEG-6000); glycerol;glycine or other amino acids; and lipids. Buffer systems for use withthe formulations include citrate; acetate; bicarbonate; and phosphatebuffers. Phosphate buffer is a commonly used excipient.

The formulation can also contain a non-ionic detergent. Examples ofnon-ionic detergents include Polysorbate 20, Polysorbate 80, TritonX-100, Triton X-114, Nonidet P-40, Octyl α-glucoside, Octyl β-glucoside,Brij 35, Pluronic, and Tween 20.

Kits & Methods of Treatment

Other aspects of the invention pertain to compositions and kitscomprising any of the compounds described herein. Accordingly, one ormore embodiments of the invention pertain to a pharmaceuticalcomposition or formulation comprising: any of the compounds according toany of formulae I-III, or a pharmaceutically acceptable salt, solvate,or prodrug thereof; and at least one pharmaceutically acceptablecarrier.

Another aspect of the invention pertains to a kit comprising: acontainer having an effective amount of any of the compounds accordingto any of formulae I-III, or a pharmaceutically acceptable salt,solvate, or prodrug thereof, or any combination of two or more thereof;and instructions for using the same to prevent and/or treat Alzheimer'sdisease and/or CAA.

Yet another aspect of the invention pertains to a method of preventingand/or treating Alzheimer's disease and/or cerebral amyloid angiopathy,the method comprising administering to a patient in need thereof atherapeutically effective amount of any of the compounds discussedabove. In some embodiments, the administration of an effective amount ofthe compound increases processing of one or more gangliosides selectedfrom GM2 and GA2.

Yet another aspect of the present invention pertains to a method forenhancing the activity of β-hexosaminidase, the method comprisingadministering a therapeutically effective amount of any of the compoundsdiscussed above.

The therapeutic agent(s) may be administered orally or parenterally,including intravenously, subcutaneously, intra-arterially,intraperitoneally, ophthalmically, intramuscularly, buccally, rectally,vaginally, intraorbitally, intracerebrally, intradermally,intracranially, intraspinally, intraventricularly, intrathecally,intracisternally, intracapsularly, intrapulmonarily, intranasally,transmucosally, transdermally, or via inhalation. In one preferredembodiment, the therapeutic agent(s) is administered orally.

Administration of therapeutic agent(s) may be by periodic injections ofa bolus of the formulation, or may be administered by intravenous orintraperitoneal administration from a reservoir which is external (e.g.,an i.v. bag) or internal (e.g., a bioerodable implant). See, e.g., U.S.Pat. Nos. 4,407,957 and 5,798,113, each incorporated herein byreference. Intrapulmonary delivery methods and apparatus are described,for example, in U.S. Pat. Nos. 5,654,007, 5,780,014, and 5,814,607, eachincorporated herein by reference. Other useful parenteral deliverysystems include ethylene-vinyl acetate copolymer particles, osmoticpumps, implantable infusion systems, pump delivery, encapsulated celldelivery, liposomal delivery, needle-delivered injection, needle-lessinjection, nebulizer, aerosolizer, electroporation, and transdermalpatch. Needle-less injector devices are described in U.S. Pat. Nos.5,879,327; 5,520,639; 5,846,233 and 5,704,911, the specifications ofwhich are herein incorporated by reference. Any of the formulationsdescribed above can be administered using these methods.

Subcutaneous injections have the advantages allowingself-administration, while also resulting in a prolonged plasmahalf-life as compared to intravenous administration. Furthermore, avariety of devices designed for patient convenience, such as refillableinjection pens and needle-less injection devices, may be used with theformulations of the present invention as discussed herein.

A suitable pharmaceutical preparation is in a unit dosage form. In suchform, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose such as maximizingsubstrate clearance.

The amount of effective therapeutic agent(s) for preventing or treatingthe referenced disorder can be determined on a case-by-case basis bythose skilled in the art, guided by the present specification and theexamples herein. The amount and frequency of administration of thetherapeutic agent(s) will be regulated according to the judgment of theattending clinician (physician) considering such factors as age,condition and size of the patient as well as risk for developingdisorder or severity of the symptoms of the referenced disorder beingtreated.

The therapeutic agent(s) of the present invention can be administered incombination with at least one other therapeutic agent. Administration ofthe therapeutic agent(s) of the present invention with at least oneother therapeutic agent is understood to encompass administration thatis sequential or concurrent. In one embodiment, the therapeutic agentsare administered in separate dosage forms. In another embodiment, two ormore therapeutic agents are administered concurrently in the same dosageform.

Reference throughout this specification to “one embodiment,” “certainembodiments,” “one or more embodiments” or “an embodiment” means that aparticular feature, structure, material, or characteristic described inconnection with the embodiment is included in at least one embodiment ofthe invention. Thus, the appearances of the phrases such as “in one ormore embodiments,” “in certain embodiments,” “in one embodiment” or “inan embodiment” in various places throughout this specification are notnecessarily referring to the same embodiment of the invention.Furthermore, the particular features, structures, materials, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It will be apparent to those skilled in the art thatvarious modifications and variations can be made to the method andapparatus of the present invention without departing from the spirit andscope of the invention. Thus, it is intended that the present inventioninclude modifications and variations that are within the scope of theappended claims and their equivalents.

What is claimed is:
 1. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt or solvate thereof.
 2. A pharmaceutical composition comprising: a. the compound of claim 1; and b. at least one pharmaceutically acceptable carrier.
 3. A method for treating Alzheimer's disease and/or cerebral amyloid angiopathy in a patient diagnosed with the same, the method comprising administering to the patient an effective amount of the compound of claim
 1. 4. The method of claim 3, wherein the administration of an effective amount of the compound increases processing of one or more gangliosides selected from GM2 and GA2.
 5. A method for enhancing the activity of β-hexosaminidase, the method comprising administering an effective amount of the compound of claim
 1. 6. A kit comprising: a. the compound of claim 1; and b. instructing for using the same to treat Alzheimer's disease and/or cerebral amyloid angiopathy.
 7. The compound of claim 1, wherein the compound comprises:

or a pharmaceutically acceptable salt or solvate thereof.
 8. The compound of claim 1, wherein the compound comprises:

or a pharmaceutically acceptable salt or solvate thereof.
 9. The compound of claim 1, wherein the compound comprises:

or a pharmaceutically acceptable salt or solvate thereof.
 10. The compound of claim 1, wherein the compound comprises:

or a pharmaceutically acceptable salt or solvate thereof.
 11. The compound of claim 1, wherein the compound comprises:

or a pharmaceutically acceptable salt or solvate thereof.
 12. The compound of claim 1, wherein the compound comprises:

or a pharmaceutically acceptable salt or solvate thereof.
 13. The compound of claim 1, wherein the compound comprises:

or a pharmaceutically acceptable salt or solvate thereof. 